The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

INPP4B overexpression and c-KIT downregulation in human achalasia.

BACKGROUND: Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS: Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS: Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES: The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.

Economic evaluation of the randomized European Achalasia trial comparing pneumodilation with Laparoscopic Heller myotomy.

BACKGROUND: A recent multicenter randomized trial in achalasia patients has shown that pneumatic dilation resulted in equivalent relief of symptoms compared to laparoscopic Heller myotomy. Additionally, the cost of each treatment should be also taken in consideration. Therefore, the aim of the present study was to perform an economic analysis of the European achalasia trial. METHODS: Patients with newly diagnosed achalasia were enrolled from to 2003 to 2008 in 14 centers in five European countries and were randomly assigned to either pneumatic dilation (PD) or laparoscopic Heller (LHM). The economic analysis was performed in the three centers in three different countries where most patients were enrolled (Amsterdam [NL], Leuven, [B] and Padova [I]) and then applied to all patients included in the study. The total raw costs of the two treatments per patient include the initial costs, the costs of complications, and the costs of retreatments. RESULTS: Two hundred and one patients, 107 (57 males and 50 females, mean age 46 CI: 43-49 years) were randomized to LHM and 94 (59 males and 34 females, mean age 46 CI 43-50 years) to PD. The total cost of PD per patient was quite comparable in the three different centers; €3397 in Padova, €3259 in Amsterdam and €3792 in Leuven. For LHM, the total costs per patient were highest in Amsterdam: €4488 in Padova, €6720 in Amsterdam, and €5856 in Leuven. CONCLUSION: In conclusion, the strategy of treating achalasia starting with PD appears the most economic approach, independent of the health system.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

[The role of consultation in palliative sedation in the central region of the Netherlands]. / De rol van consultatie bij palliatieve sedatie in de regio Midden-Nederland.

OBJECTIVE: To gain insight into the role of consultation in palliative sedation. DESIGN: Retrospective analysis. METHOD: All consultation records of the Palliation Team Midden Nederland (PTMN) from 1 November 2005 to 31 October 2006 were analysed. If palliative sedation was mentioned in the record, the following variables were listed: character of the consultation, data of the questioner, patient data, consultation question, indication for palliative sedation, and character of the advice given. RESULTS: Palliative sedation was a topic in 206 of the 659 consultation records investigated (31%). Intractable delirium, pain, exhaustion, dyspnoea and nausea or vomiting were the most important grounds for palliative sedation. In 47 of the 113 consultations (41%) about starting palliative sedation a negative advice was given, and this was nearly always because there were no intractable somatic symptoms. Existential problems played an important role in 14 of these 113 consultations (12%). In 25 consultations (22%) euthanasia versus palliative sedation was considered explicitly. For these cases there was hardly ever an indication for sedation. CONCLUSION: Palliative sedation was an important reason for consulting the PTMN. The high percentage of negative advice indicates that consultation about palliative sedation has an added value. It gives the questioner the opportunity to check whether all options for treatment have been tried. The question as to whether existential problems are an indication for palliative sedation should be discussed between medical professionals as well as publicly. Palliative sedation rarely is an alternative for euthanasia.

Pre-operative injections of epoetin-alpha versus post-operative retransfusion of autologous shed blood in total hip and knee replacement: a prospective randomised clinical trial.

This prospective randomised clinical trial evaluated the effect of alternatives for allogeneic blood transfusions after total hip replacement and total knee replacement in patients with pre-operative haemoglobin levels between 10.0 g/dl and 13.0 g/dl. A total of 100 patients were randomly allocated to the Eprex (pre-operative injections of epoetin) or Bellovac groups (post-operative retransfusion of shed blood). Allogeneic blood transfusions were administered according to hospital policy. In the Eprex group, 4% of the patients (two patients) received at least one allogeneic blood transfusion. In the Bellovac group, where a mean 216 ml (0 to 700) shed blood was retransfused, 28% (14 patients) required the allogeneic transfusion (p = 0.002). When comparing Eprex with Bellovac in total hip replacement, the percentages were 7% (two of 30 patients) and 30% (nine of 30 patients) (p = 0.047) respectively, whereas in total knee replacement, the percentages were 0% (0 of 20 patients) and 25% (five of 20 patients) respectively (p = 0.042). Pre-operative epoetin injections are more effective but more costly in reducing the need for allogeneic blood transfusions in mildly anaemic patients than post-operative retransfusion of autologous blood.

Peri-operative blood management in elective orthopaedic surgery. A critical review of the literature.

Blood loss during orthopaedic procedures can be extensive and the need for allogeneic blood is a common requirement. However, blood transfusion conceals a number of well-recognised risks and complications and blood products have become more expensive because of their specific preparation procedure. Surgical technique, awareness of the problem and restriction of transfusion triggers are important factors affecting the management of blood loss. Several studies have additionally shown the efficacy of epoetin injections in increasing the pre-operative haemoglobin level. On the other hand, the true benefit of pre-operative autologous donation, acute normovolemic haemodilution and COX-2 selective NSAIDs remains under dispute. Regarding the role of platelet rich plasmapheresis, fibrin sealing and anti-fibinolytic drugs more data are needed. Hypotensive epidural anaesthesia seems to be an advantageous method in minimising peri-operative blood loss. However, this is not a widely performed technique in orthopaedic surgery. In addition, post-operative blood cell saving systems after total knee or hip arthroplasty have been reported to significantly minimise allogeneic blood transfusions when compared to control groups. It can be concluded that many interventions diminish more or less allogeneic blood transfusion in elective orthopaedic surgery. Nevertheless more prospective studies are needed and appropriate algorithms should be applied in peri-operative blood loss management. This review presents an overview of the available interventions which aim to diminish the use of allogeneic blood in elective orthopaedic surgery.